1. Field of Invention
This invention relates to a novel process for making antibacterial cephalosporins from allenylazetidinone derivatives.
More specifically, as shown in Scheme (A), the process involves converting 2-(3-amino-2-oxo-azetidin-1-yl)-2,3-butadienoate of formula I into C-3 aromatic heterocyclicthio, arylthio, aromatic heterocyclicsulfonyl, or arylsulfonyl cephalosporins of formula II and further replacing said C-3 group with a group such as cis-propenyl found in cefprozil, a broad spectrum antibiotic. ##STR2## In Scheme (A), R.sup.1, R.sup.2, R.sup.3, R.sup.4, and n are defined hereinbelow. Preferable reagents used in step 1 and step 2 are lithium halide and an organo-stannane, n-Bu.sub.3 SnR.sup.4, along with a palladium (0) catalyst, respectively.
2. Description of Related Art
Farina et al., in Tetrahedron Letters, 29, No. 47, p. 6043 (1988), disclose reactions of C-3 trifloxy cephalosporins of formula IV with organo-stannanes in the presence of a palladium (0) catalyst to transfer a variety of R.sup.6 radicals. Examples of R.sup.6 radicals include alkenyl, alkynyl and aryl. ##STR3##
The instant process of displacing the C-3 aromatic heterocylicthio, arylthio, aromatic heterocyclicsulfonyl or arylsulfonyl group with a R.sup.4 group using an organo-stannane reagent and a palladium (0) catatylst has never been reported.
Conway et al., in the Canadian Journal of Chemistry, 56, p 1335 (1978), disclose the allene derivative of formula VI. ##STR4## Due to the direct attachment of a methylene group to the C-4 position of the azetidinone ring, the compound of formula VI cannot be directly converted to a cephem structure.
U.S. Pat. No. 4,066,641, issued to Hamashima et al. on Jan. 3, 1978, discloses a process of cephem preparation, as depicted in Scheme (C), by a base induced ring closure of compound of formula VII. ##STR5## wherein A is amino or substituted amino;
COB is carboxy or protected carboxy; PA1 R.sup.7 -S can be substituted thio such as benzothiazol-2-ylthio, thiazol-2-ylthio and acetylthio; PA1 Y is an electron drawing group from acyloxy, halogen, cyano, nitro and nitroso; and the dotted line shows .DELTA..sup.2 or .DELTA..sup.3 double bond. PA1 hydrogen; PA1 C.sub.1-6 alkyl, C.sub.1-6 alkyl substituted by cyano, carboxy, halogen, amino, C.sub.1-6 alkyloxy, C.sub.1-6 alkylthio, trifluoromethyl, or trifluoromethylthio; PA1 a phenyl or substituted phenyl group represented by the formula ##STR13## wherein R.sup.b and R.sup.c independently are hydrogen, halogen, hydroxy, C.sub.1-6 alkyloxy, C.sub.1-6 alkyl, C.sub.1-6 alkylthio, amino, mono- or di(C.sub.1-6 alkyl)amino, C.sub.1-6 alkanoylamino, C.sub.1-6 alkylsulfonylamino, carboxy, carbamoyl, hydroxymethyl, aminomethyl, or carboxymethyl; PA1 a group presented by the formula ##STR14## wherein R.sup.b and R.sup.c have the same meanings as defined above, D is oxygen or sulfur, and m is 0 or 1; PA1 a heteroarylmethyl group represented by the formula EQU R.sup.d --CH.sub.2 -- PA1 wherein R.sup.d is thienyl, furyl, benzothienyl, benzofuryl, indolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, and such heteroaryl groups substituted by amino, hydroxy, halogen, C.sub.1-6 alkyl, C.sub.1-6 alkyloxy, C.sub.1-6 alkysulfonylamino; PA1 a substituted methyl group represented by the formula ##STR15## wherein R.sup.e is oyclohexa-1,4-dienyl, or a phenyl group or substituted phenyl group ##STR16## wherein R.sup.b and R.sup.c have the above defined meanings, or R.sup.e is R.sup.d as defined above, and Z is hydroxy, C.sub.1-6 alkanoyloxy, carboxy, sulfo, or amino; PA1 a keto group or an oximino-substituted group represented by the formulae ##STR17## wherein R.sup.f is R.sup.d or R.sup.e as defined above and R.sup.g is hydrogen, C.sub.1-6 alkyl, cyclic C.sub.3-6 alkyl or a radical selected from the formulae ##STR18## in which R.sup.h and R.sup.i are independently hydrogen, methyl or ethyl, or R.sup.h and R.sup.i, taken together with the carbon atom to which they are attached, may be a cycloalkylidene ring containing from 3 to 5 carbon atoms, R.sup.k and R.sup.m are hydrogen or carboxy, with the proviso that both cannot be the same, and R.sup.n is hydrogen or acetyl; or PA1 an alkylidene group of the formulae ##STR19## in which L is halogen or CF.sub.3, and R.sup.f, R.sup.i and R.sup.h are as defined above. PA1 FAB: Fast Atom Bombardment PA1 DMSO: dimethyl sulfoxide PA1 Boc: t-butoxycarbonyl PA1 DPM: diphenylmethyl PA1 Ph: phenyl PA1 tBu: t-butyl PA1 HPLC: High pressure liquid chromatography PA1 PNB: 4-nitrobenzyl PA1 Tf: trifluoromethanesulfonyl
The present invention provides methods for the exclusive formation of the .DELTA..sup.3 cephem isomers.
Similar to the process depicted in Scheme (C) above, U.S. Pat. No. 4,147,864, issued to Woodward et al. on Apr. 3, 1979, relates to a base promoted cyclization of the compounds of formula IX into the cephems of formula X ##STR6## wherein R.sup.8 is an acyl group; R.sup.9 represents an optionally substituted aromatic heterocyclic radical with up to 15, preferably up to 9, carbon atoms and at least one ring nitrogen atom and optionally a further ring hetero-atom, such as oxygen or sulfur, which radical is bonded to the thio group --S-- by one of its ring carbon atoms, which is bonded to a ring nitrogen atom by a double bond, or R.sup.9 is --SO.sub.2 Q' in which Q' is an optionally substituted aliphatic, cycloaliphatic, araliphatic or aromatic hydrocarbon with up to 18, preferably up to 10, carbon atoms; R.sup.10 includes a group such as lower alkyl; and R.sup.11 represents hydrogen or a carboxy protecting group.
U.S. Pat. No. 4,550,162 issued to Woodward et al., on Oct. 29, 1985, discloses compounds similar to cephalosporins of formula IX above in which R.sup.8, R.sup.9 and R.sup.11 have the same meaning as above, but R.sup.10 has the meaning of --SO.sub.2 Q' as defined above.
U.S. Pat. 4,267,340, issued on May 12, 1981 to Kamiya et al., discloses, inter alia, the azetidinone derivatives of the formula XI. As shown in Scheme (E), the azetidinones of formula XI can be converted into the cephams of formula XII with an electrophilic reagent X.sub.2 such as chlorine. ##STR7## In Scheme (E), R.sup.13 represents a substituted or unsubstituted amino radical; R.sup.12 is a substituted or unsubstituted heterocyclic group such as oxazolyl, benzoxazolyl, thiazolyl, benzothiazolyl, benzimidazolinyl and imidazolinyl; R.sup.11 is hydrogen or a carboxy protecting group.
U.S. Pat. No. 4,798,890, issued to Torii et al. on Jan. 17, 1989, relates to the formation of the compounds of formula XIV, which are reported to be useful precursors to cephems, from the compounds of formula XIII. ##STR8## In formulae XIII and XIV, R.sup.15 can represent amino or acylamino, R.sup.14 is a substituted or unsubstituted nitrogen-containing aromatic heterocyclic residue, R.sup.11 is hydrogen or a carboxy protecting group, and R.sup.16 is substituted or unsubstituted phenyl.
A number of C-3 aromatic heterocyclicthio cephems are already known. For example Hamashima et al., in Heterocycles, 5, p. 419 (1976), and Scartazzini et al., in [Helvetica Chimica Acta, 58, p 2437 (1975) disclose the cephems of formulae XV and XVI, respectively. ##STR9## Typically, C-3 aromatic heterocyclicthio cephems such as shown as structures XV and XVI have been made by the displacement of a C-3 leaving group with an aromatic heterocyclic mercaptan. For example, Farina et al., in the Journal of Organic Chemistry, 54, p. 4962 (1989), disclose triflate (trifluorosulfonyloxy) as such C-3 leaving group. To Applicants knowledge, none of the syntheses of the C-3 aromatic heterocyclicthio cephems reported to date has involved direct cyclization of 2-(2-oxo-azetidin-l-yl)-2,3-butadienoates [allenylazetidinones] of formula I of the present application.
Kant et al., in Tetrahedron Letters. 31, No. 24, p. 3389 (1990), disclose the reaction of the compound of formula XVI with lithium dimethylmethyl cuprate to afford the compound of formula V'. ##STR10## However, the art does not teach that organo-stannanes can be used in lieu of the cuprates to displace C-3 aromatic heterocylicthio groups in cephalosporins.